A Novel FK506-Like Binding Protein Interacts with the Glucocorticoid Receptor and Regulates Steroid Receptor Signaling

Abstract

FKBP-like (FKBPL) protein is a novel immunophilin-like protein that plays a role in the cellular stress response. Its three tetratricopeptide repeat motifs are homologous to the heat shock protein 90 interaction sites of other immunophilins that have roles in steroid hormone receptor signaling. In this study, using biomolecular complementation and coimmunoprecipitation techniques, we show that FKBPL also colocalizes and interacts with the components of the heat shock protein 90-glucocorticoid receptor (GR) complex and demonstrate that the PPIase domain of FKBPL is important for the interaction between this complex and the dynein motor protein, dynamitin. Treatment of DU145 cells with the GR ligand, dexamethasone, induced a rapid and coordinated translocation of both GR and FKBPL to the nucleus; this response was perturbed when FKBPL was knocked down with a targeted small interfering RNA. Furthermore, overexpression of FKBPL increased GR protein levels and transactivation of a luciferase reporter gene in response to dexamethasone in DU145 cells. However, these responses were cell line dependent. In summary, these data suggest that FKBPL can be classed as a new member of the FKBP protein family with a role in steroid receptor complexes and signaling.

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

“…FKBPL has previously been linked with the GR/Hsp90 chaperone complex, with implications for GR translocation and signaling (15). We have now determined that FKBPL is also involved in the ERα/Hsp90 chaperone complex with consequences for downstream estrogenic signaling and response to endocrine therapy.…”

“…We hypothesized that FKBPL might bind Hsp90 within ER chaperone complexes in breast cancer cells, especially because we had already identified a role for this protein in glucocorticoid/Hsp90 complexes (15). Using the mammalian two-hybrid assay, the expression constructs pBIND-FKBPL and pACT-Hsp90 were cotransfected into ER-positive MCF-7 cells and the binding ability of FKBPL with Hsp90 was assessed by measuring luciferase activity derived from a GAL4-driven luciferase reporter.…”

“…In support of this association, FKBPL has been implicated in Hsp90-dependent stabilization of newly synthesized p21 by preventing its proteosomal degradation (13); also, overexpression of FKBPL inhibits cell cycle progression at the G 0 -G 1 phase in leukemic cells (14). More recently, a role for FKBPL in Hsp90-associated steroid hormone receptor complexes was identified in which FKBPL regulated glucocorticoid receptor (GR) protein levels, transcriptional activation, and cellular localization in prostate cancer cells (15).…”

Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway

“…FKBPL was identified as having a role in the response of cells to radiation (21,22). In a complex with Hsp90, FKBPL stabilizes p21 (23) and regulates estrogen receptor (ER), androgen receptor, and glucocorticoid receptor signaling (2,24,25). Furthermore, in breast cancer, because of FKBPL's association with ER, FKBPL has shown potential as both a prognostic and predictive biomarker of response to endocrine therapy (2,26).…”

The hsp90-FKBP52 Complex Links the Mineralocorticoid Receptor to Motor Proteins and Persists Bound to the Receptor in Early Nuclear Events

“…They belong to the relatively conserved large family of proteins known as immunophilins (IMMs) (48). Among the members of this family, some IMMs have been recovered in steroid receptor-hsp90 complexes, i.e., FKBP52, FKBP51, CyP40, and three IMM-like proteins, protein phosphatase 5 (PP5), XAP2/ARA9, and WISp39 (33,44). Even though the biological function of these proteins in the receptor-hsp90 heterocomplex remains poorly understood, it is thought that these IMMs are not related directly to the immunosuppressant effect.…”